AAN Annual Meeting

VANCOUVER – The antioxidant edaravone was associated with less deterioration in functional rating and quality of life scales when started early in the course of amyotrophic lateral sclerosis (ALS), based on results from a set of trials conducted in Japan and reported at the annual meeting of the American Academy of Neurology.

Edaravone is thought to confer neuroprotection in part through its free radical–scavenging activity and first garnered interest for the treatment of acute ischemic stroke, according to presenting author Dr. Joseph M. Palumbo, vice president and head of Clinical Research at Mitsubishi Tanabe Pharma Development America, the maker of edaravone. It is now approved in several countries for that indication.

Susan London/Frontline Medical News

In a pivotal randomized phase III trial, Dr. Palumbo and his colleagues studied 137 patients who had definite or probable ALS, were less than 2 years out from symptom onset, had normal respiratory function, and were able to perform most activities of daily living. All patients received standard of care, usually including riluzole (Rilutek), plus either edaravone (MCI-186) or placebo.

After 24 weeks of treatment, compared with placebo, edaravone was associated with a smaller decline in scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) (–5.01 vs. –7.50; difference between groups, 2.49; P = .0013), according to data reported in a poster session at the meeting.

Significant benefit was seen on the limb and bulbar subscales, and there was a trend favoring edaravone on the respiratory subscale. Additionally, patients given edaravone had comparatively less deterioration in quality of life as assessed with the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) (P = .03). Grip strength did not differ between groups, and there were no deaths in either group.

“We are not aware of any other positive phase III study in maybe a generation, since riluzole, in ALS. So we are showing this data and we are hopeful that people are as excited as we are,” Dr. Palumbo said in an interview.

In the area of safety, edaravone and placebo did not differ significantly with respect to the rate of adverse events, with contusion, dysphagia, and constipation predominating. The most common serious adverse event was dysphagia, seen in 12% of each group.

The trial’s findings led to approval of edaravone for treatment of ALS in Japan, where it is marketed as Radicut. Additionally, the U.S. Food and Drug Administration (FDA) granted edaravone orphan drug designation for ALS but has not approved it for this indication.

An additional 24-week open-label extension study among 123 patients from the trial, in which all received the drug regardless of their initially assigned treatment, showed that the benefit of edaravone was durable. Patients who continued treatment with the drug had less of a decline from baseline in ALSFRS-R score than did peers switched to the drug from placebo (difference between groups, 4.17; P = .004), according to data reported in another poster. Also, the former had a lower risk of death (P = .019) and less decline in lung function. Meanwhile, the drug’s safety profile remained good.

The researchers are preparing their findings for journal submission and are revisiting the drug’s regulatory status in the United States, according to Dr. Palumbo. “We’re talking to the FDA now. We’ve got our fingers crossed.”

There is no compelling reason to think that the drug’s efficacy in the U.S. population would differ from that in the Japanese population, but that will ultimately be an issue for regulators to decide, he said.

It is difficult to compare edaravone with other ALS treatment options, as all patients in the trial concomitantly received standard of care, Dr. Palumbo explained. “We can only speak about standard of care, and we think that we’ve improved on standard of care here,” he maintained.

The initial phase III trial of edaravone in ALS, which enrolled a population having a wider range of disease severity, failed to meet its primary endpoint of improvement in ALSFRS-R score (Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:610-7). An extension study in 181 patients, also reported in a poster at the meeting, supported post hoc findings hinting that the timing of drug initiation was important.

“We learned a tremendous amount in that study about who the patients were who would ultimately benefit,” Dr. Palumbo commented. “We had a number of hypotheses. One hypothesis was that if we found patients who in fact were still functional at baseline and who really had the diagnosis – they had either definite or probable ALS – and still had very good respiratory function, that we would likely find a signal there.”

Rounding out the set of trials was a small randomized placebo-controlled trial among 25 patients with more advanced ALS, done at the request of Japanese health authorities. Results showed that edaravone was safe in this population but had no clear benefit.

Dr. Palumbo disclosed that he is an employee of Mitsubishi Tanabe Pharma Development America, Inc. The trials were sponsored by Mitsubishi Tanabe Pharma Corporation.

VANCOUVER – The antioxidant edaravone was associated with less deterioration in functional rating and quality of life scales when started early in the course of amyotrophic lateral sclerosis (ALS), based on results from a set of trials conducted in Japan and reported at the annual meeting of the American Academy of Neurology.

Edaravone is thought to confer neuroprotection in part through its free radical–scavenging activity and first garnered interest for the treatment of acute ischemic stroke, according to presenting author Dr. Joseph M. Palumbo, vice president and head of Clinical Research at Mitsubishi Tanabe Pharma Development America, the maker of edaravone. It is now approved in several countries for that indication.

Susan London/Frontline Medical News

In a pivotal randomized phase III trial, Dr. Palumbo and his colleagues studied 137 patients who had definite or probable ALS, were less than 2 years out from symptom onset, had normal respiratory function, and were able to perform most activities of daily living. All patients received standard of care, usually including riluzole (Rilutek), plus either edaravone (MCI-186) or placebo.

After 24 weeks of treatment, compared with placebo, edaravone was associated with a smaller decline in scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) (–5.01 vs. –7.50; difference between groups, 2.49; P = .0013), according to data reported in a poster session at the meeting.

Significant benefit was seen on the limb and bulbar subscales, and there was a trend favoring edaravone on the respiratory subscale. Additionally, patients given edaravone had comparatively less deterioration in quality of life as assessed with the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) (P = .03). Grip strength did not differ between groups, and there were no deaths in either group.

“We are not aware of any other positive phase III study in maybe a generation, since riluzole, in ALS. So we are showing this data and we are hopeful that people are as excited as we are,” Dr. Palumbo said in an interview.

In the area of safety, edaravone and placebo did not differ significantly with respect to the rate of adverse events, with contusion, dysphagia, and constipation predominating. The most common serious adverse event was dysphagia, seen in 12% of each group.

The trial’s findings led to approval of edaravone for treatment of ALS in Japan, where it is marketed as Radicut. Additionally, the U.S. Food and Drug Administration (FDA) granted edaravone orphan drug designation for ALS but has not approved it for this indication.

An additional 24-week open-label extension study among 123 patients from the trial, in which all received the drug regardless of their initially assigned treatment, showed that the benefit of edaravone was durable. Patients who continued treatment with the drug had less of a decline from baseline in ALSFRS-R score than did peers switched to the drug from placebo (difference between groups, 4.17; P = .004), according to data reported in another poster. Also, the former had a lower risk of death (P = .019) and less decline in lung function. Meanwhile, the drug’s safety profile remained good.

The researchers are preparing their findings for journal submission and are revisiting the drug’s regulatory status in the United States, according to Dr. Palumbo. “We’re talking to the FDA now. We’ve got our fingers crossed.”

There is no compelling reason to think that the drug’s efficacy in the U.S. population would differ from that in the Japanese population, but that will ultimately be an issue for regulators to decide, he said.

It is difficult to compare edaravone with other ALS treatment options, as all patients in the trial concomitantly received standard of care, Dr. Palumbo explained. “We can only speak about standard of care, and we think that we’ve improved on standard of care here,” he maintained.

The initial phase III trial of edaravone in ALS, which enrolled a population having a wider range of disease severity, failed to meet its primary endpoint of improvement in ALSFRS-R score (Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:610-7). An extension study in 181 patients, also reported in a poster at the meeting, supported post hoc findings hinting that the timing of drug initiation was important.

“We learned a tremendous amount in that study about who the patients were who would ultimately benefit,” Dr. Palumbo commented. “We had a number of hypotheses. One hypothesis was that if we found patients who in fact were still functional at baseline and who really had the diagnosis – they had either definite or probable ALS – and still had very good respiratory function, that we would likely find a signal there.”

Rounding out the set of trials was a small randomized placebo-controlled trial among 25 patients with more advanced ALS, done at the request of Japanese health authorities. Results showed that edaravone was safe in this population but had no clear benefit.

Dr. Palumbo disclosed that he is an employee of Mitsubishi Tanabe Pharma Development America, Inc. The trials were sponsored by Mitsubishi Tanabe Pharma Corporation.

VANCOUVER – The antioxidant edaravone was associated with less deterioration in functional rating and quality of life scales when started early in the course of amyotrophic lateral sclerosis (ALS), based on results from a set of trials conducted in Japan and reported at the annual meeting of the American Academy of Neurology.

Edaravone is thought to confer neuroprotection in part through its free radical–scavenging activity and first garnered interest for the treatment of acute ischemic stroke, according to presenting author Dr. Joseph M. Palumbo, vice president and head of Clinical Research at Mitsubishi Tanabe Pharma Development America, the maker of edaravone. It is now approved in several countries for that indication.

Susan London/Frontline Medical News

In a pivotal randomized phase III trial, Dr. Palumbo and his colleagues studied 137 patients who had definite or probable ALS, were less than 2 years out from symptom onset, had normal respiratory function, and were able to perform most activities of daily living. All patients received standard of care, usually including riluzole (Rilutek), plus either edaravone (MCI-186) or placebo.

After 24 weeks of treatment, compared with placebo, edaravone was associated with a smaller decline in scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) (–5.01 vs. –7.50; difference between groups, 2.49; P = .0013), according to data reported in a poster session at the meeting.

Significant benefit was seen on the limb and bulbar subscales, and there was a trend favoring edaravone on the respiratory subscale. Additionally, patients given edaravone had comparatively less deterioration in quality of life as assessed with the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) (P = .03). Grip strength did not differ between groups, and there were no deaths in either group.

“We are not aware of any other positive phase III study in maybe a generation, since riluzole, in ALS. So we are showing this data and we are hopeful that people are as excited as we are,” Dr. Palumbo said in an interview.

In the area of safety, edaravone and placebo did not differ significantly with respect to the rate of adverse events, with contusion, dysphagia, and constipation predominating. The most common serious adverse event was dysphagia, seen in 12% of each group.

The trial’s findings led to approval of edaravone for treatment of ALS in Japan, where it is marketed as Radicut. Additionally, the U.S. Food and Drug Administration (FDA) granted edaravone orphan drug designation for ALS but has not approved it for this indication.

An additional 24-week open-label extension study among 123 patients from the trial, in which all received the drug regardless of their initially assigned treatment, showed that the benefit of edaravone was durable. Patients who continued treatment with the drug had less of a decline from baseline in ALSFRS-R score than did peers switched to the drug from placebo (difference between groups, 4.17; P = .004), according to data reported in another poster. Also, the former had a lower risk of death (P = .019) and less decline in lung function. Meanwhile, the drug’s safety profile remained good.

The researchers are preparing their findings for journal submission and are revisiting the drug’s regulatory status in the United States, according to Dr. Palumbo. “We’re talking to the FDA now. We’ve got our fingers crossed.”

There is no compelling reason to think that the drug’s efficacy in the U.S. population would differ from that in the Japanese population, but that will ultimately be an issue for regulators to decide, he said.

It is difficult to compare edaravone with other ALS treatment options, as all patients in the trial concomitantly received standard of care, Dr. Palumbo explained. “We can only speak about standard of care, and we think that we’ve improved on standard of care here,” he maintained.

The initial phase III trial of edaravone in ALS, which enrolled a population having a wider range of disease severity, failed to meet its primary endpoint of improvement in ALSFRS-R score (Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:610-7). An extension study in 181 patients, also reported in a poster at the meeting, supported post hoc findings hinting that the timing of drug initiation was important.

“We learned a tremendous amount in that study about who the patients were who would ultimately benefit,” Dr. Palumbo commented. “We had a number of hypotheses. One hypothesis was that if we found patients who in fact were still functional at baseline and who really had the diagnosis – they had either definite or probable ALS – and still had very good respiratory function, that we would likely find a signal there.”

Rounding out the set of trials was a small randomized placebo-controlled trial among 25 patients with more advanced ALS, done at the request of Japanese health authorities. Results showed that edaravone was safe in this population but had no clear benefit.

Dr. Palumbo disclosed that he is an employee of Mitsubishi Tanabe Pharma Development America, Inc. The trials were sponsored by Mitsubishi Tanabe Pharma Corporation.

VANCOUVER – Dimethyl fumarate and fingolimod appear to have an edge over other disease-modifying therapies for multiple sclerosis (MS) in real-world practice, according to a comparative effectiveness study reported at the annual meeting of the American Academy of Neurology.

Dr. Jacqueline A. Nicholas, a neuroimmunologist and MS specialist with the OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, and her colleagues analyzed claims data from 5,004 commercially insured adults with MS in the United States who started treatment with any of five oral and injectable disease-modifying therapies.

Susan London/Frontline Medical News

Findings reported at the meeting showed that dimethyl fumarate netted the greatest reduction in annualized relapse rate, at one-third, followed by fingolimod, at about one-fourth. The adjusted risk of relapse in the year after drug initiation was significantly higher for interferon-beta, glatiramer acetate, and teriflunomide, compared with dimethyl fumarate.

“Right now, a lot of the data that we have to use in the clinic is based on clinical trials data. That’s often not what we see in the real world, the MS centers, and even the outpatient neurology setting,” Dr. Nicholas said in an interview. “This study is nice just because it points out that when you look at real-world data, it shows, yes, that these drugs work, and that some of the initial benefit for the oral disease-modifying therapies is what we thought. Obviously, we don’t have cross-trial comparisons to make from the clinical trials, so this is real data that we can actually use in our clinic setting.”

The findings are also helpful given changing health care models and ongoing issues with reimbursement and obtaining insurance approval to use various drugs, she added. “These are things that we can show to those payers as to why it’s important that we have these therapies and that we be able to decide as MS specialists what’s going to be best for the patient.

“Right now, the biggest challenge in the MS world is that obviously, as an MS specialist, you have a lot of experience and knowledge. And based on poor prognostic factors, when somebody comes in, you may not want to go with an escalation model [of treatment], where you are starting with something that a payer may think we should start with, an injectable,” Dr. Nicholas added. “Somebody may have more aggressive disease, and maybe you are going to want to start with an oral or an IV drug. But the payers are the ones right now who have the say. So it’s a lot of time and a lot of work [getting insurance approval], and while you are fighting to get what you know your patient needs, your patient’s suffering, accumulating disability, and possibly having more relapses.”

For the study, the investigators analyzed administrative data from the Truven MarketScan Commercial Claims Databases for 2012 through 2014.

Analyses were based on 2,564 patients treated with dimethyl fumarate (brand name Tecfidera), 735 with interferon-beta (Rebif, Avonex, Betaseron, and Extavia), 827 with glatiramer acetate (Copaxone), 417 with teriflunomide (Aubagio), and 461 with fingolimod (Gilenya).

Comparing the year before and the year after drug initiation, only dimethyl fumarate and fingolimod were associated with significant reductions in the annualized relapse rate, according to findings reported in a poster session. The reductions were 33% and 27%, respectively.

In the postinitiation year and with dimethyl fumarate as the comparator, the adjusted incidence rate ratio for relapse was similar for fingolimod but significantly higher for glatiramer acetate (1.28), interferon-beta (1.25), and teriflunomide (1.28).

“I don’t think that these findings are surprising,” Dr. Nicholas said. “I work in a large MS center and I would say this is generally what I see clinically in terms of the effectiveness. So it’s more reassuring to me than anything.”

She acknowledged that safety and tolerability will also come into play when selecting among disease-modifying therapies. “Those data are incredibly important, and we certainly balance that. With a health care claims database, that’s hard data to pull unless you are looking at one specific [adverse effect], but that’s something that needs to be very carefully weighed with the efficacy data for the patient,” she said.

In a companion study also reported in the poster session, the investigators compared the impact of starting the same five drugs on health care costs and utilization.

Results of that study showed that total health care costs rose in the postinitiation year for all five drugs, with the increase ranging from $38,801 for dimethyl fumarate to $52,352 for fingolimod.

However, total nonprescription medical costs decreased across the board, apparently driven by both less use of outpatient services and fewer inpatient hospital stays, with the greatest reduction seen for dimethyl fumarate.

Dr. Nicholas disclosed that she has received research funding from Genzyme, Novartis, Teva, Biogen, and Alexion, and has received consulting and speaking honoraria from Genzyme, Novartis, Teva, Biogen, and Medtronic. The study was supported by Biogen.

VANCOUVER – Dimethyl fumarate and fingolimod appear to have an edge over other disease-modifying therapies for multiple sclerosis (MS) in real-world practice, according to a comparative effectiveness study reported at the annual meeting of the American Academy of Neurology.

Dr. Jacqueline A. Nicholas, a neuroimmunologist and MS specialist with the OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, and her colleagues analyzed claims data from 5,004 commercially insured adults with MS in the United States who started treatment with any of five oral and injectable disease-modifying therapies.

Susan London/Frontline Medical News

Findings reported at the meeting showed that dimethyl fumarate netted the greatest reduction in annualized relapse rate, at one-third, followed by fingolimod, at about one-fourth. The adjusted risk of relapse in the year after drug initiation was significantly higher for interferon-beta, glatiramer acetate, and teriflunomide, compared with dimethyl fumarate.

“Right now, a lot of the data that we have to use in the clinic is based on clinical trials data. That’s often not what we see in the real world, the MS centers, and even the outpatient neurology setting,” Dr. Nicholas said in an interview. “This study is nice just because it points out that when you look at real-world data, it shows, yes, that these drugs work, and that some of the initial benefit for the oral disease-modifying therapies is what we thought. Obviously, we don’t have cross-trial comparisons to make from the clinical trials, so this is real data that we can actually use in our clinic setting.”

The findings are also helpful given changing health care models and ongoing issues with reimbursement and obtaining insurance approval to use various drugs, she added. “These are things that we can show to those payers as to why it’s important that we have these therapies and that we be able to decide as MS specialists what’s going to be best for the patient.

“Right now, the biggest challenge in the MS world is that obviously, as an MS specialist, you have a lot of experience and knowledge. And based on poor prognostic factors, when somebody comes in, you may not want to go with an escalation model [of treatment], where you are starting with something that a payer may think we should start with, an injectable,” Dr. Nicholas added. “Somebody may have more aggressive disease, and maybe you are going to want to start with an oral or an IV drug. But the payers are the ones right now who have the say. So it’s a lot of time and a lot of work [getting insurance approval], and while you are fighting to get what you know your patient needs, your patient’s suffering, accumulating disability, and possibly having more relapses.”

For the study, the investigators analyzed administrative data from the Truven MarketScan Commercial Claims Databases for 2012 through 2014.

Analyses were based on 2,564 patients treated with dimethyl fumarate (brand name Tecfidera), 735 with interferon-beta (Rebif, Avonex, Betaseron, and Extavia), 827 with glatiramer acetate (Copaxone), 417 with teriflunomide (Aubagio), and 461 with fingolimod (Gilenya).

Comparing the year before and the year after drug initiation, only dimethyl fumarate and fingolimod were associated with significant reductions in the annualized relapse rate, according to findings reported in a poster session. The reductions were 33% and 27%, respectively.

In the postinitiation year and with dimethyl fumarate as the comparator, the adjusted incidence rate ratio for relapse was similar for fingolimod but significantly higher for glatiramer acetate (1.28), interferon-beta (1.25), and teriflunomide (1.28).

“I don’t think that these findings are surprising,” Dr. Nicholas said. “I work in a large MS center and I would say this is generally what I see clinically in terms of the effectiveness. So it’s more reassuring to me than anything.”

She acknowledged that safety and tolerability will also come into play when selecting among disease-modifying therapies. “Those data are incredibly important, and we certainly balance that. With a health care claims database, that’s hard data to pull unless you are looking at one specific [adverse effect], but that’s something that needs to be very carefully weighed with the efficacy data for the patient,” she said.

In a companion study also reported in the poster session, the investigators compared the impact of starting the same five drugs on health care costs and utilization.

Results of that study showed that total health care costs rose in the postinitiation year for all five drugs, with the increase ranging from $38,801 for dimethyl fumarate to $52,352 for fingolimod.

However, total nonprescription medical costs decreased across the board, apparently driven by both less use of outpatient services and fewer inpatient hospital stays, with the greatest reduction seen for dimethyl fumarate.

Dr. Nicholas disclosed that she has received research funding from Genzyme, Novartis, Teva, Biogen, and Alexion, and has received consulting and speaking honoraria from Genzyme, Novartis, Teva, Biogen, and Medtronic. The study was supported by Biogen.

VANCOUVER – Dimethyl fumarate and fingolimod appear to have an edge over other disease-modifying therapies for multiple sclerosis (MS) in real-world practice, according to a comparative effectiveness study reported at the annual meeting of the American Academy of Neurology.

Dr. Jacqueline A. Nicholas, a neuroimmunologist and MS specialist with the OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, and her colleagues analyzed claims data from 5,004 commercially insured adults with MS in the United States who started treatment with any of five oral and injectable disease-modifying therapies.

Susan London/Frontline Medical News

Findings reported at the meeting showed that dimethyl fumarate netted the greatest reduction in annualized relapse rate, at one-third, followed by fingolimod, at about one-fourth. The adjusted risk of relapse in the year after drug initiation was significantly higher for interferon-beta, glatiramer acetate, and teriflunomide, compared with dimethyl fumarate.

“Right now, a lot of the data that we have to use in the clinic is based on clinical trials data. That’s often not what we see in the real world, the MS centers, and even the outpatient neurology setting,” Dr. Nicholas said in an interview. “This study is nice just because it points out that when you look at real-world data, it shows, yes, that these drugs work, and that some of the initial benefit for the oral disease-modifying therapies is what we thought. Obviously, we don’t have cross-trial comparisons to make from the clinical trials, so this is real data that we can actually use in our clinic setting.”

The findings are also helpful given changing health care models and ongoing issues with reimbursement and obtaining insurance approval to use various drugs, she added. “These are things that we can show to those payers as to why it’s important that we have these therapies and that we be able to decide as MS specialists what’s going to be best for the patient.

“Right now, the biggest challenge in the MS world is that obviously, as an MS specialist, you have a lot of experience and knowledge. And based on poor prognostic factors, when somebody comes in, you may not want to go with an escalation model [of treatment], where you are starting with something that a payer may think we should start with, an injectable,” Dr. Nicholas added. “Somebody may have more aggressive disease, and maybe you are going to want to start with an oral or an IV drug. But the payers are the ones right now who have the say. So it’s a lot of time and a lot of work [getting insurance approval], and while you are fighting to get what you know your patient needs, your patient’s suffering, accumulating disability, and possibly having more relapses.”

For the study, the investigators analyzed administrative data from the Truven MarketScan Commercial Claims Databases for 2012 through 2014.

Analyses were based on 2,564 patients treated with dimethyl fumarate (brand name Tecfidera), 735 with interferon-beta (Rebif, Avonex, Betaseron, and Extavia), 827 with glatiramer acetate (Copaxone), 417 with teriflunomide (Aubagio), and 461 with fingolimod (Gilenya).

Comparing the year before and the year after drug initiation, only dimethyl fumarate and fingolimod were associated with significant reductions in the annualized relapse rate, according to findings reported in a poster session. The reductions were 33% and 27%, respectively.

In the postinitiation year and with dimethyl fumarate as the comparator, the adjusted incidence rate ratio for relapse was similar for fingolimod but significantly higher for glatiramer acetate (1.28), interferon-beta (1.25), and teriflunomide (1.28).

“I don’t think that these findings are surprising,” Dr. Nicholas said. “I work in a large MS center and I would say this is generally what I see clinically in terms of the effectiveness. So it’s more reassuring to me than anything.”

She acknowledged that safety and tolerability will also come into play when selecting among disease-modifying therapies. “Those data are incredibly important, and we certainly balance that. With a health care claims database, that’s hard data to pull unless you are looking at one specific [adverse effect], but that’s something that needs to be very carefully weighed with the efficacy data for the patient,” she said.

In a companion study also reported in the poster session, the investigators compared the impact of starting the same five drugs on health care costs and utilization.

Results of that study showed that total health care costs rose in the postinitiation year for all five drugs, with the increase ranging from $38,801 for dimethyl fumarate to $52,352 for fingolimod.

However, total nonprescription medical costs decreased across the board, apparently driven by both less use of outpatient services and fewer inpatient hospital stays, with the greatest reduction seen for dimethyl fumarate.

Dr. Nicholas disclosed that she has received research funding from Genzyme, Novartis, Teva, Biogen, and Alexion, and has received consulting and speaking honoraria from Genzyme, Novartis, Teva, Biogen, and Medtronic. The study was supported by Biogen.

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

aotto@frontlinemedcom.com

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

aotto@frontlinemedcom.com

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

aotto@frontlinemedcom.com

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

aotto@frontlinemedcom.com

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

aotto@frontlinemedcom.com

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

aotto@frontlinemedcom.com

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – In a study at New York University, it took 27 healthy, native English–speaking volunteers 42.8 seconds to complete the King-Devick concussion screening test, which is about average for nonconcussed subjects.

However, it took 27 other volunteers with English as a second language 54.4 seconds (P = .001). Had the test been given on the sidelines instead of in a laboratory, the extra 12 seconds might easily have been mistaken as a sign of serious concussion because concussions generally add about 5 seconds to the King-Devick score.

“A prolongation of 12 seconds in non-native English speakers has real clinical implications,” said lead investigator Katharine Dempsey, a medical student and member of the eye movement research team in the department of neurology at New York University.

King-Devick (KD) is an increasingly popular sideline screening tool used widely in professional sports. Subjects are timed on how long it takes to read out loud and in English three sets of 40 numbers, with each set progressively more difficult to read. It’s administered by flashcards or, as in the study, by computer screen.

All of the non-native speakers at NYU were largely proficient in English, but their native languages – 18 in total, most often Spanish or Chinese – were often dominant, meaning they were used at home and to work out mental arithmetic. Some subjects did not use Roman numerals or right-to-left reading in their native tongues.

KD instructions recommend testing subjects against their own preseason baseline scores; the NYU findings emphasize how important that is when subjects aren’t native English speakers. The investigators are concerned that when baseline scores are unavailable, non-native English speakers will be scored against reference ranges for native speakers.

“There’s incredible utility in using a sideline concussion screening test, but we definitely have to get out the message that the best practice is to take an athlete’s own preseason baseline. We have to be incredibly cautious when comparing test times of non-native English speakers to a normative database for native speakers,” Ms. Dempsey said at the annual meeting of the American Academy of Neurology.

The participants were in their early 30s, on average, and had no histories of concussion. The majority were women, and most were NYU employees or their friends.

The team also tracked eye movements during testing. Non-native speakers had more quick eye movement (149 vs. 135; P = .03), but also fixated longer on numbers before initiating eye movement (345.4 milliseconds vs. 288.0; P = .007). Lag time correlated with native language dominance and suggests longer processing time.

The next step is to test how well patients do with KD testing in their native language, Ms. Dempsey said.

Ms. Dempsey had no disclosures.

aotto@frontlinemedcom.com

VANCOUVER – In a study at New York University, it took 27 healthy, native English–speaking volunteers 42.8 seconds to complete the King-Devick concussion screening test, which is about average for nonconcussed subjects.

However, it took 27 other volunteers with English as a second language 54.4 seconds (P = .001). Had the test been given on the sidelines instead of in a laboratory, the extra 12 seconds might easily have been mistaken as a sign of serious concussion because concussions generally add about 5 seconds to the King-Devick score.

“A prolongation of 12 seconds in non-native English speakers has real clinical implications,” said lead investigator Katharine Dempsey, a medical student and member of the eye movement research team in the department of neurology at New York University.

King-Devick (KD) is an increasingly popular sideline screening tool used widely in professional sports. Subjects are timed on how long it takes to read out loud and in English three sets of 40 numbers, with each set progressively more difficult to read. It’s administered by flashcards or, as in the study, by computer screen.

All of the non-native speakers at NYU were largely proficient in English, but their native languages – 18 in total, most often Spanish or Chinese – were often dominant, meaning they were used at home and to work out mental arithmetic. Some subjects did not use Roman numerals or right-to-left reading in their native tongues.

KD instructions recommend testing subjects against their own preseason baseline scores; the NYU findings emphasize how important that is when subjects aren’t native English speakers. The investigators are concerned that when baseline scores are unavailable, non-native English speakers will be scored against reference ranges for native speakers.

“There’s incredible utility in using a sideline concussion screening test, but we definitely have to get out the message that the best practice is to take an athlete’s own preseason baseline. We have to be incredibly cautious when comparing test times of non-native English speakers to a normative database for native speakers,” Ms. Dempsey said at the annual meeting of the American Academy of Neurology.

The participants were in their early 30s, on average, and had no histories of concussion. The majority were women, and most were NYU employees or their friends.

The team also tracked eye movements during testing. Non-native speakers had more quick eye movement (149 vs. 135; P = .03), but also fixated longer on numbers before initiating eye movement (345.4 milliseconds vs. 288.0; P = .007). Lag time correlated with native language dominance and suggests longer processing time.

The next step is to test how well patients do with KD testing in their native language, Ms. Dempsey said.

Ms. Dempsey had no disclosures.

aotto@frontlinemedcom.com

VANCOUVER – In a study at New York University, it took 27 healthy, native English–speaking volunteers 42.8 seconds to complete the King-Devick concussion screening test, which is about average for nonconcussed subjects.

However, it took 27 other volunteers with English as a second language 54.4 seconds (P = .001). Had the test been given on the sidelines instead of in a laboratory, the extra 12 seconds might easily have been mistaken as a sign of serious concussion because concussions generally add about 5 seconds to the King-Devick score.

“A prolongation of 12 seconds in non-native English speakers has real clinical implications,” said lead investigator Katharine Dempsey, a medical student and member of the eye movement research team in the department of neurology at New York University.

King-Devick (KD) is an increasingly popular sideline screening tool used widely in professional sports. Subjects are timed on how long it takes to read out loud and in English three sets of 40 numbers, with each set progressively more difficult to read. It’s administered by flashcards or, as in the study, by computer screen.

All of the non-native speakers at NYU were largely proficient in English, but their native languages – 18 in total, most often Spanish or Chinese – were often dominant, meaning they were used at home and to work out mental arithmetic. Some subjects did not use Roman numerals or right-to-left reading in their native tongues.

KD instructions recommend testing subjects against their own preseason baseline scores; the NYU findings emphasize how important that is when subjects aren’t native English speakers. The investigators are concerned that when baseline scores are unavailable, non-native English speakers will be scored against reference ranges for native speakers.

“There’s incredible utility in using a sideline concussion screening test, but we definitely have to get out the message that the best practice is to take an athlete’s own preseason baseline. We have to be incredibly cautious when comparing test times of non-native English speakers to a normative database for native speakers,” Ms. Dempsey said at the annual meeting of the American Academy of Neurology.

The participants were in their early 30s, on average, and had no histories of concussion. The majority were women, and most were NYU employees or their friends.

The team also tracked eye movements during testing. Non-native speakers had more quick eye movement (149 vs. 135; P = .03), but also fixated longer on numbers before initiating eye movement (345.4 milliseconds vs. 288.0; P = .007). Lag time correlated with native language dominance and suggests longer processing time.

The next step is to test how well patients do with KD testing in their native language, Ms. Dempsey said.

Ms. Dempsey had no disclosures.

aotto@frontlinemedcom.com